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Quercetin inhibited LPS-induced cytokine storm by interacting with the AKT1-FoxO1 and Keap1-Nrf2 signaling pathway in macrophages

Xu et al., Scientific Reports, doi:10.1038/s41598-024-71569-y
Sep 2024  
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Quercetin for COVID-19
24th treatment shown to reduce risk in July 2021
 
*, now with p = 0.0031 from 11 studies.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,800+ studies for 95 treatments. c19early.org
In Silico, In Vitro, and mouse study showing that quercetin inhibits LPS-induced cytokine storm by interacting with the AKT1-FoxO1 and Keap1-Nrf2 signaling pathways in macrophages. Authors found quercetin effectively suppressed the overexpression of pro-inflammatory mediators like IL-6, TNF-α, IL-1β, and MCP-1 in LPS-stimulated Raw264.7 cells and in vivo in C57BL/6 mice. Quercetin regulated the AKT1-FoxO1 pathway by increasing AKT1 phosphorylation and inhibiting FoxO1 nuclear translocation, thereby reducing inflammatory gene expression. It also activated the Keap1-Nrf2 pathway, decreasing intracellular reactive oxygen species (ROS) levels and oxidative stress. Molecular docking showed quercetin had the strongest binding affinity to AKT1 among potential targets. In mice, quercetin pretreatment reduced inflammatory factors in bronchoalveolar lavage fluid and ameliorated LPS-induced lung tissue damage. The study suggests quercetin's potential as a therapeutic agent for cytokine storm, by modulating key inflammatory and antioxidant pathways in macrophages.
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
64 preclinical studies support the efficacy of quercetin for COVID-19:
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,4,5,17,19,20,25,33,34,36,37,55,56, MproB,2,4,6,8,10,12,13,15,18,19,25,29,31-33,37,38,40,56,57, RNA-dependent RNA polymeraseC,4,27, PLproD,32,40, ACE2E,17,18,23,32,36,56, TMPRSS2F,17, helicaseG,24,29, endoribonucleaseH,34, cathepsin LI,21, Wnt-3J,17, FZDK,17, LRP6L,17, ezrinM,35, ADRPN,33, NRP1O,36, EP300P,11, PTGS2Q,18, HSP90AA1R,11,18, matrix metalloproteinase 9S,26, IL-6T,16,30, IL-10U,16, VEGFAV,30, and RELAW,30 proteins. In Vitro studies demonstrate inhibition of the MproB,10,45,52 protein, and inhibition of spike-ACE2 interactionX,41. In Vitro studies demonstrate efficacy in Calu-3Y,44, A549Z,16, HEK293-ACE2+AA,51, Huh-7AB,20, Caco-2AC,43, Vero E6AD,14,37,43, mTECAE,46, and RAW264.7AF,46 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAG,48, db/db miceAH,46,54, BALB/c miceAI,53, and rats58. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice53 and inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages1.
Xu et al., 8 Sep 2024, China, peer-reviewed, 11 authors. Contact: yicheng6834@126.com, lzjradiotherapy@163.com, huangying68@163.com.
This PaperQuercetinAll
Quercetin inhibited LPS-induced cytokine storm by interacting with the AKT1-FoxO1 and Keap1-Nrf2 signaling pathway in macrophages
Jingyi Xu, Yue Li, Xi Yang, Hong Li, Xi Xiao, Jia You, Huawei Li, Lingnan Zheng, Cheng Yi, Zhaojun Li, Ying Huang
Scientific Reports, doi:10.1038/s41598-024-71569-y
Cytokine storm (CS) emerges as an exacerbated inflammatory response triggered by various factors such as pathogens and excessive immunotherapy, posing a significant threat to life if left unchecked. Quercetin, a monomer found in traditional Chinese medicine, exhibits notable anti-inflammatory and antiviral properties. This study endeavors to explore whether quercetin intervention could mitigate CS through a combination of network pharmacology analysis and experimental validation. First, common target genes and potential mechanisms affected by quercetin and CS were identified through network pharmacology, and molecular docking experiments confirmed quercetin and core targets. Subsequently, in vitro experiments of Raw264.7 cells stimulated by lipopolysaccharide (LPS) showed that quercetin could effectively inhibit the overexpression of pro-inflammatory mediators and regulate the AKT1-FoxO1 signaling pathway. At the same time, quercetin can reduce ROS through the Keap1-Nrf2 signaling pathway. In addition, in vivo studies of C57BL/6 mice injected with LPS further confirmed quercetin's inhibitory effect on CS. In conclusion, this investigation elucidated novel target genes and signaling pathways implicated in the therapeutic effects of quercetin on CS. Moreover, it provided compelling evidence supporting the efficacy of quercetin in reversing LPS-induced CS, primarily through the regulation of the AKT1-FoxO1 and Keap1-Nrf2 signaling pathways.
Author contributions Xu, Li, Yang, Li, Xiao, You, Li, Zheng, Li, Yi, and Huang contributed to this study. Xu, Li,ang contributed equally to this study. Yi, Li andHuang directed the design of this study, supervised its implementation and revised draft. Competing interests The authors declare no competing interests.
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Res.'}, { 'issue': '6', 'key': '71569_CR24', 'doi-asserted-by': 'publisher', 'first-page': '1202', 'DOI': '10.1097/HJH.0b013e328329e31c', 'volume': '27', 'author': 'F Simon', 'year': '2009', 'unstructured': 'Simon, F. & Fernández, R. Early lipopolysaccharide-induced reactive ' 'oxygen species production evokes necrotic cell death in human umbilical ' 'vein endothelial cells. J. Hypertens. 27(6), 1202–1216 (2009).', 'journal-title': 'J. Hypertens.'}, { 'key': '71569_CR25', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.1155/2016/2795090', 'volume': '2016', 'author': 'H-Y Tan', 'year': '2016', 'unstructured': 'Tan, H.-Y. et al. The reactive oxygen species in macrophage ' 'polarization: Reflecting its dual role in progression and treatment of ' 'human diseases. Oxid. Med. Cell. Longevity 2016, 1–16 (2016).', 'journal-title': 'Oxid. Med. Cell. 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Drug Discov.'}, { 'issue': '12', 'key': '71569_CR28', 'doi-asserted-by': 'publisher', 'first-page': '6368', 'DOI': '10.4049/jimmunol.1202574', 'volume': '190', 'author': 'C-S Yang', 'year': '2013', 'unstructured': 'Yang, C.-S. et al. TLR3-triggered reactive oxygen species contribute to ' 'inflammatory responses by activating signal transducer and activator of ' 'transcription-1. J. Immunol. 190(12), 6368–6377 (2013).', 'journal-title': 'J. Immunol.'}, { 'key': '71569_CR29', 'doi-asserted-by': 'publisher', 'first-page': '19', 'DOI': '10.3390/ijms231911740', 'volume': '23', 'author': 'D Jarczak', 'year': '2022', 'unstructured': 'Jarczak, D. & Nierhaus, A. Cytokine storm—definition, causes, and ' 'implications. Int. J. Mol. Sci. 23, 19 (2022).', 'journal-title': 'Int. J. Mol. Sci.'}, { 'key': '71569_CR30', 'doi-asserted-by': 'publisher', 'first-page': '1', 'DOI': '10.1136/jitc-2020-000892', 'volume': '8', 'author': 'A Addeo', 'year': '2020', 'unstructured': 'Addeo, A., Obeid, M. & Friedlaender, A. COVID-19 and lung cancer: Risks, ' 'mechanisms and treatment interactions. J. ImmunoTherapy Cancer 8, 1 ' '(2020).', 'journal-title': 'J. ImmunoTherapy Cancer'}, { 'key': '71569_CR31', 'first-page': '12', 'volume': '2021', 'author': 'R Knoll', 'year': '2021', 'unstructured': 'Knoll, R., Schultze, J. L. & Schulte-Schrepping, J. Monocytes and ' 'Macrophages in COVID-19. Front. Immunol. 2021, 12 (2021).', 'journal-title': 'Front. Immunol.'}, { 'issue': '2', 'key': '71569_CR32', 'doi-asserted-by': 'publisher', 'first-page': '188', 'DOI': '10.1182/blood-2014-05-552729', 'volume': '124', 'author': 'DW Lee', 'year': '2014', 'unstructured': 'Lee, D. W. et al. Current concepts in the diagnosis and management of ' 'cytokine release syndrome. 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The neutrophil-to-lymphocyte ratio determines clinical ' 'efficacy of corticosteroid therapy in patients with COVID-19. Cell ' 'Metabol. 33(2), 258-269.e3 (2021).', 'journal-title': 'Cell Metabol.'}, { 'issue': '16', 'key': '71569_CR40', 'doi-asserted-by': 'publisher', 'first-page': '1503', 'DOI': '10.1056/NEJMoa2028700', 'volume': '384', 'author': 'IO Rosas', 'year': '2021', 'unstructured': 'Rosas, I. O. et al. Tocilizumab in hospitalized patients with severe ' 'Covid-19 pneumonia. N. Engl. J. Med. 384(16), 1503–1516 (2021).', 'journal-title': 'N. Engl. J. Med.'}, { 'key': '71569_CR41', 'doi-asserted-by': 'publisher', 'first-page': '8', 'DOI': '10.1371/journal.pone.0237693', 'volume': '15', 'author': 'A Ip', 'year': '2020', 'unstructured': 'Ip, A. et al. Hydroxychloroquine and tocilizumab therapy in COVID-19 ' 'patients-An observational study. Plos One 15, 8 (2020).', 'journal-title': 'Plos One'}, { 'key': '71569_CR42', 'first-page': '109', 'volume': '2022', 'author': 'J-Y Kang', 'year': '2022', 'unstructured': 'Kang, J.-Y. et al. Melatonin attenuates LPS-induced pyroptosis in acute ' 'lung injury by inhibiting NLRP3-GSDMD pathway via activating Nrf2/HO-1 ' 'signaling axis. Int. Immunopharmacol. 2022, 109 (2022).', 'journal-title': 'Int. Immunopharmacol.'}, { 'issue': '8', 'key': '71569_CR43', 'doi-asserted-by': 'publisher', 'first-page': '1198', 'DOI': '10.1016/j.bcp.2005.12.031', 'volume': '71', 'author': 'JH Kim', 'year': '2006', 'unstructured': 'Kim, J. H. et al. Rengyolone inhibits inducible nitric oxide synthase ' 'expression and nitric oxide production by down-regulation of NF-κB and ' 'p38 MAP kinase activity in LPS-stimulated RAW 264.7 cells. Biochem. ' 'Pharmacol. 71(8), 1198–1205 (2006).', 'journal-title': 'Biochem. Pharmacol.'}, { 'key': '71569_CR44', 'doi-asserted-by': 'publisher', 'first-page': '9', 'DOI': '10.3390/cells11091391', 'volume': '11', 'author': 'SV Suryavanshi', 'year': '2022', 'unstructured': 'Suryavanshi, S. V., Zaiachuk, M., Pryimak, N., Kovalchuk, I. & ' 'Kovalchuk, O. Cannabinoids alleviate the LPS-induced cytokine storm via ' 'attenuating NLRP3 inflammasome signaling and TYK2-mediated STAT3 ' 'signaling pathways in vitro. Cells 11, 9 (2022).', 'journal-title': 'Cells'}, { 'key': '71569_CR45', 'first-page': '102', 'volume': '2022', 'author': 'H Li', 'year': '2022', 'unstructured': 'Li, H. et al. Glycyrrhetinic acid: A potential drug for the treatment of ' 'COVID-19 cytokine storm. Phytomedicine 2022, 102 (2022).', 'journal-title': 'Phytomedicine'}, { 'key': '71569_CR46', 'first-page': '13', 'volume': '2022', 'author': 'J You', 'year': '2022', 'unstructured': 'You, J. et al. Inspiration for COVID-19 treatment: Network analysis and ' 'experimental validation of baicalin for cytokine storm. Front. ' 'Pharmacol. 2022, 13 (2022).', 'journal-title': 'Front. Pharmacol.'}, { 'key': '71569_CR47', 'doi-asserted-by': 'crossref', 'unstructured': 'Lin. X, Zhao. Q, Fu. B, Xiong. Y, Zhang. S, Xu. S, Wu. H. ISOC1 ' 'Modulates Inflammatory Responses in Macrophages through the ' 'AKT1/PEX11B/Peroxisome Pathway. Molecules 27(18), 5896 (2022).', 'DOI': '10.3390/molecules27185896'}, { 'key': '71569_CR48', 'doi-asserted-by': 'publisher', 'unstructured': 'Wang. R, Wang. Y, Wu. J, Guo. Y, Xiao. H, Zhang. Y, & Ma. K. Resveratrol ' 'Targets AKT1 to Inhibit Inflammasome Activation in Cardiomyocytes Under ' 'Acute Sympathetic Stress. Frontiers in Pharmacology 13, ' 'https://doi.org/10.3389/fphar.2022.818127 (2022).', 'DOI': '10.3389/fphar.2022.818127'}, { 'key': '71569_CR49', 'doi-asserted-by': 'publisher', 'unstructured': 'Yang. J, Cheng. M, Gu. B, & Wang. J. CircRNA_09505 aggravates ' 'inflammation and joint damage in collagen-induced arthritis mice via ' 'miR-6089/AKT1/NF-κBaxis, Cell Death & Disease 11(10), ' 'https://doi.org/10.1038/s41419-020-03038-z (2020).', 'DOI': '10.1038/s41419-020-03038-z'}, { 'issue': '24', 'key': '71569_CR50', 'doi-asserted-by': 'publisher', 'first-page': '9517', 'DOI': '10.1073/pnas.1119038109', 'volume': '109', 'author': 'A Arranz', 'year': '2012', 'unstructured': 'Arranz, A. et al. Akt1 and Akt2 protein kinases differentially ' 'contribute to macrophage polarization. Proc. Natl. Acad. Sci. 109(24), ' '9517–9522 (2012).', 'journal-title': 'Proc. Natl. Acad. Sci.'}, { 'key': '71569_CR51', 'doi-asserted-by': 'publisher', 'first-page': '777', 'DOI': '10.1038/ni1221', 'volume': '6', 'author': 'M Martin', 'year': '2005', 'unstructured': 'Martin, M. et al. Toll-like receptor-mediated cytokine production is ' 'differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6, ' '777–784 (2005).', 'journal-title': 'Nat. Immunol.'}, { 'issue': '4', 'key': '71569_CR52', 'doi-asserted-by': 'publisher', 'first-page': '1603', 'DOI': '10.4049/jimmunol.1200596', 'volume': '190', 'author': 'F Seiler', 'year': '2013', 'unstructured': 'Seiler, F. et al. FOXO transcription factors regulate innate immune ' 'mechanisms in respiratory epithelial cells. J. Immunol. 190(4), ' '1603–1613 (2013).', 'journal-title': 'J. Immunol.'}, { 'key': '71569_CR53', 'first-page': '9', 'volume': '2018', 'author': 'K Sun', 'year': '2018', 'unstructured': 'Sun, K. et al. Schisandrin attenuates lipopolysaccharide-induced lung ' 'injury by regulating TLR-4 and Akt/FoxO1 signaling pathways. Front. ' 'Physiol. 2018, 9 (2018).', 'journal-title': 'Front. Physiol.'}, { 'key': '71569_CR54', 'first-page': '16', 'volume': '22', 'author': 'J Lee', 'year': '2021', 'unstructured': 'Lee, J., Jang, J., Park, S.-M. & Yang, S.-R. An update on the role of ' 'Nrf2 in respiratory disease: Molecular mechanisms and therapeutic ' 'approaches. Int. J. Mol. Sci. 22, 16 (2021).', 'journal-title': 'Int. J. Mol. Sci.'}, { 'key': '71569_CR55', 'doi-asserted-by': 'publisher', 'first-page': 'e0216711', 'DOI': '10.1371/journal.pone.0216711', 'volume': '14', 'author': 'X Lin', 'year': '2019', 'unstructured': 'Lin, X. et al. Curcumin attenuates oxidative stress in RAW264.7 cells by ' 'increasing the activity of antioxidant enzymes and activating the ' 'Nrf2-Keap1 pathway. PloS one 14, e0216711 (2019).', 'journal-title': 'PloS one'}, { 'key': '71569_CR56', 'doi-asserted-by': 'publisher', 'first-page': '111079', 'DOI': '10.1016/j.intimp.2023.111079', 'volume': '125', 'author': 'X Liu', 'year': '2023', 'unstructured': 'Liu, X. et al. Mollugin prevents CLP-induced sepsis in mice by ' 'inhibiting TAK1-NF-κB/MAPKs pathways and activating Keap1-Nrf2 pathway ' 'in macrophages. Int. 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